|
Current Estimates from
the National Health Interview Survey,
NCHS.
1996. 1999 Oct, Series 10(200). Atlanta, GA: National
Center for Health Statistics/Centers for Disease Control
and Prevention/U.S. Department of Health and Human
Services.
What Are Kidney
Stones?
NIDDK.
1998. Bethesda, MD: National Institute of Diabetes
& Digestive & Kidney
Diseases/National Institutes of Health
(www.niddk.nih.gov).
Kidney Diseases Dictionary
Index
NIDDK.
1999. Bethesda, MD: National Institute of Diabetes
& Digestive & Kidney Diseases/National
Institutes of Health (www.niddk.nih.gov).
Anemia in Kidney Disease
and Dialysis
NIDDK.
2001a Apr. Bethesda, MD: National Institute of Diabetes
& Digestive & Kidney Diseases/National
Institutes of Health (www.niddk.nih.gov).
Kidney and Urologic
Diseases Statistics for the United States
NIDDK.
2001b Dec. Bethesda, MD: National Institute of Diabetes
& Digestive & Kidney Diseases/National
Institutes of Health (www.niddk.nih.gov).
Renal Disease
Overview
NORD.
2002. Universal City, CA: National Organization for
Renal Disease
(www.stop-ersd.org).
Modification of
polycystic kidney disease and fatty acid status by soy
protein diet.
Ogborn MR, Nitschmann E, Weiler HA, Bankovic-Calic
N.
Department of Pediatrics and Child Health, University of
Manitoba, Winnipeg,
Manitoba, Canada.
Kidney Int. 2000 Jan;57(1):159-66.
Modification of polycystic kidney disease and fatty acid
status by soy protein diet. BACKGROUND: Previous studies
have demonstrated that soy protein can slow progression of
renal injury in the Han:SPRD-cy rat. We undertook a study
to establish whether this benefit was independent of any
nutritional deprivation, and whether or not it was
associated with changes in polyunsaturated fatty acid
status that have been previously linked to the
anti-inflammatory or antineoplastic potential of soy diets.
METHODS: Male Han:SPRD-cy rats were pair fed a 20% casein
or 20% soy protein diet for six weeks from weaning. Tissue
was harvested for analysis of cystic change, cell
proliferation, macrophage
infiltration, and fibrosis. Renal and hepatic tissues were
also harvested for lipid analysis using gas chromatography.
RESULTS: Animals thrived on both diets. Soy protein feeding
was associated with reduced cystic change (4.3 vs. 7.0
mL/kg, P < 0.0001), epithelial cell proliferation
(15.7 vs. 21.0 cells/mm epithelium, P < 0.0001),
macrophage infiltration (25.3 vs. 43.5 cells/high-power
field, P < 0.0001), and fibrosis (0.6 vs. 1.07
mL/kg, P < 0.0001). The soy diet prevented a
significant elevation in serum creatinine in diseased
versus normal animals. Soy feeding was associated with
higher renal and hepatic linoleic acid content and higher
hepatic alpha-linolenic acid, but lower hepatic
arachidonic
acid content. CONCLUSIONS: Isocaloric soy protein feeding
ameliorates both
epithelial and interstitial changes in the Han:SPRD-cy rat
independent of a
hypocholesterolemic effect. The histologic benefit is
associated with changes in
polyunsaturated fatty acid metabolism that may influence
both inflammatory and
proliferative pathways.
[Calcium decreases
urinary oxalate] [Article in Japanese]
Ohgitani S, Fujita T.
Division of Laboratory and Research, National Sanatorium
Hyogo Chuo Hospital.
Nippon Ronen Igakkai Zasshi. 2000 Oct;37(10):805-10.
The effects of calcium supplementation on urinary
oxalate excretion was tested in 9 normal subjects, 4 males
and 5 females between 23 and 49 years of age. In a
crossover study 800 mg calcium was orally administered as
active absorbable algal calcium (AAACa) (A) and calcium
carbonate (B), and compared with non-calcium containing
placebo (C). Calcium, oxalate, osmolality, creatinine and
pH were measured in the first three morning urine samples
and Ca/osmolality, Ca/osmolality/body weight, Ca/creatinine
and oxalate/osmolality were calculated to correct for urine
dilution. Ca x oxalate product was also calculated and Ca
oxalate crystal in the sediment was microscopically
examined and
semiquantitatively estimated as -, +, ++, and +++
expressed as 0, 1, 2 and 3
respectively. Urinary Ca excretion was similar in A and B,
but significantly larger than C, regardless of the method
of correction for dilution. Urinary oxalate excretion
tended to be lower in A than in B and C. Urine pH was
similar among all three groups. Ca x oxalate product was
higher in C than in A and B. AAACa, unlike calcium
carbonate, appeared to decrease urinary oxalate excretion
and Ca x oxalate product more efficiently than Ca
carbonate, suggesting a possibility of inhibiting the
formation of Ca x oxalate kidney stones. Formation of
calcium oxalate was also tested in vitro by adding oxalate
to urine samples and aqueous calcium solution.
Protective effects of
dietary phytoestrogens in chronic renal
disease.
Ranich T, Bhathena SJ, Velasquez MT.
Division of Renal Diseases and Hypertension, Department of
Medicine, George
Washington University Medical Center, Washington, DC
20037, USA.
J Ren Nutr. 2001 Oct;11(4):183-93.
Phytoestrogens are naturally occuring plant compounds
that are present primarily in soybeans as isoflavones and
in flaxseed as lignans. Because of their structural
similarity to endogenous estrogens, phytoestrogens bind to
both estrogen receptors (ER)-alpha and beta (but more
strongly to ER-beta) and exert estrogen-like effects. There
is increasing evidence that dietary phytoestrogens have a
beneficial role in chronic renal disease. Nutritional
intervention studies have shown that consumption of
soy-based protein and flaxseed reduces proteinuria and
attenuates renal functional or structural damage in animals
and humans with various forms of chronic renal disease. It
is not clear which
component(s) of the soybean or flaxseed is (are)
responsible for the protective effects observed in
experimental animals and in limited studies in humans.
Vegetable protein has been shown to have a beneficial
effect on renal disease in animals and humans. Thus, the
role of soy and flaxseed cannot be ruled out. Isoflavones
and lignans are readily absorbed from the gut and converted
to active metabolites, which may be partly responsible for
the beneficial renal effects of soy protein and flaxseed.
In addition, an interaction between type of protein and
phytoestrogens is also possible. The biological actions of
isoflavones and lignans have been well defined in different
cell types in vitro and also in vivo, but how these
compounds might reduce renal injury remains to be
elucidated. Possible mechanisms include inhibition of cell
growth and proliferation via ER-mediated mechanisms or
non-ER-mediated pathways through inhibition of tyrosine
protein kinases, modulation of growth factors involved in
extracellular matrix synthesis and fibrogenesis, inhibition
of cytokine-induced activation of transcription factors,
inhibition of angiogenesis, antioxidative action,
suppression of platelet activating factor and platelet
aggregation, and immunomodulatory activity. To date,
clinical trials in humans are few, of relatively short
duration, and involve a small number of patients.
Prospective randomized trials are needed to evaluate the
long-term safety and effectiveness of dietary
phytoestrogens on renal disease progression in patients
with chronic renal failure. Copyright 2001 by the National
Kidney Foundation, Inc.
In vivo protection of
dna damage associated apoptotic and necrotic cell deaths
during acetaminophen-induced nephrotoxicity,
amiodarone-induced lung toxicity and doxorubicin-induced
cardiotoxicity by a novel IH636 grape seed proanthocyanidin
extract.
Ray SD, Patel D, Wong V, Bagchi D.
Division of Pharmacology, Toxicology and Medicinal
Chemistry, Arnold & Marie
Schwartz College of Pharmacy and Health Sciences Long
Island University,
Brooklyn, NY 11201, USA. sray@liu.edu
Res Commun Mol Pathol Pharmacol.
2000;107(1-2):137-66.
Grape seed extract, primarily a mixture of
proanthocyanidins, has been shown to
modulate a wide-range of biological, pharmacological and
toxicological effects which are mainly cytoprotective. This
study assessed the ability of IH636 grape seed
proanthocyanidin extract (GSPE) to prevent acetaminophen
(AAP)-induced nephrotoxicity, amiodarone (AMI)-induced lung
toxicity, and doxorubicin (DOX)-induced cardiotoxicity in
mice. Experimental design consisted of four groups: control
(vehicle alone), GSPE alone, drug alone and GSPE+drug. For
the cytoprotection study, animals were orally gavaged 100
mg/Kg GSPE for 7-10 days followed by i.p. injections of
organ specific three drugs (AAP: 500 mg/Kg for 24 h; AMI:
50 mg/Kg/day for four days; DOX: 20 mg/Kg for 48 h).
Parameters of study included analysis of serum chemistry
(ALT, BUN and CPK), and orderly fragmentation of genomic
DNA (both endonuclease-dependent and independent) in
addition to microscopic evaluation of damage and/or
protection in corresponding PAS stained tissues. Results
indicate that GSPE preexposure prior to AAP, AMI and DOX,
provided near complete protection in terms of serum
chemistry changes (ALT, BUN and CPK), and significantly
reduced DNA fragmentation. Histopathological examination of
kidney, heart and lung sections revealed moderate to
massive tissue damage with a variety of morphological
aberrations by all the three drugs in the absence of GSPE
preexposure than in its presence. GSPE+drug exposed tissues
exhibited minor residual damage or near total recovery.
Additionally, histopathological alterations mirrored both
serum chemistry changes and the pattern of DNA
fragmentation. Interestingly, all the drugs, such as, AAP,
AMI and DOX induced apoptotic death in addition to necrosis
in the respective organs which was very effectively blocked
by GSPE. Since AAP, AMI and DOX undergo biotransformation
and are known to produce damaging radicals in vivo, the
protection by GSPE may be linked to both inhibition of
metabolism and/or detoxification of cytotoxic radicals. In
addition, its' presumed contribution to DNA repair may be
another important attribute, which played a role in the
chemoprevention process. Additionally, this may have been
the first report on AMI-induced apoptotic death in the lung
tissue. Taken together, these events undoubtedly establish
GSPE's abundant bioavailability, and the power to defend
multiple target organs from toxic assaults induced by
structurally diverse and functionally different entities in
vivo.
Hyperhomocysteinemia
confers an independent increased risk of atherosclerosis in
end-stage renal disease and is closely linked to plasma
folate and pyridoxine concentrations.
Robinson K, Gupta A, Dennis V, Arheart K, Chaudhary D,
Green R, Vigo P, Mayer EL, Selhub J, Kutner M, Jacobsen
DW
Department of Cardiology, Cleveland Clinic Foundation, OH
44195, USA
robinsk@ccsmtp.ccf.org
Circulation 1996 Dec 1;94(11):2743-8
BACKGROUND: A high level of total plasma homocysteine is
a risk factor for
atherosclerosis, which is an important cause of death in
renal failure We evaluated the role of this as a risk
factor for vascular complications of end-stage renal
disease.
METHODS AND RESULTS: Total fasting plasma homocysteine
and other risk factors were documented in 176 dialysis
patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years).
Folate, vitamin B12, and pyridoxal phosphate concentrations
were also determined. The prevalence of high total
homocysteine values was determined by comparison with a
normal reference population, and the risk of associated
vascular complications was estimated by multiple logistic
regression. Total homocysteine concentration was higher in
patients than in the normal population (26.6 +/- 1.5 versus
10.1 +/- 1.7 mumol/L; P < .01). Abnormally high
concentrations (> 95th percentile for control
subjects, 16.3 mumol/L) were seen in 149 patients (85%)
with end-stage renal disease (P < .001). Patients
with a homocysteine concentration in the upper two
quintiles
(> 27.8 mumol/L) had an independent odds ratio of
2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B
vitamin levels were lower in patients with vascular
complications than in those without. Vitamin B6 deficiency
was more frequent in patients than in the normal reference
population (18% versus 2%; P < .01).
CONCLUSIONS: A high total plasma homocysteine
concentration is an independent risk factor for
atherosclerotic complications of end-stage renal disease.
Such patients may benefit from higher doses of B vitamins
than those currently recommended.
Effect of mineral water
containing calcium and magnesium on calcium oxalate
urolithiasis risk factors.
Rodgers AL
Department of Chemistry, University of Cape Town, South
Africa
allenr@psipsy.uct.ac.za
Urol Int 1997;58(2):93-9
Calcium oxalate kidney stone formers are invariably
advised to increase their fluid intake. In addition,
magnesium therapy is often administered. Recently, a
prospective study showed that a high dietary intake of
calcium reduces the risk of symptomatic kidney stones. The
present study was performed to test whether simultaneous
delivery of these factors--high fluid intake, magnesium
ingestion and increased dietary calcium-could reduce the
risk of calcium oxalate kidney stone formation. A French
mineral water, containing calcium and magnesium (202 and 36
ppm, respectively) was selected as the dietary vehicle.
Twenty calcium oxalate stone-forming patients of each sex
as well as 20 healthy volunteers of each sex participated
in the study. Each subject provided a 24-hour
urine collection after ingestion of mineral water over a
period of 3 days; after a suitable rest period the protocol
was repeated using local tap water (Ca: 13 ppm, Mg: 1 ppm).
In addition, 24-hour urines were collected by each subject
on their free diets. The entire cycle was repeated at least
twice by each subject. Several risk factors (excretion of
oxalate; relative supersaturations of calcium oxalate,
brushite and uric acid; calcium oxalate metastable limit;
oxalate:magnesium ratio and oxalate:metastable limit ratio)
were favourably altered by the mineral water and tap water
regimens but the former was more effective. In addition,
the mineral water protocol produced favourable but unique
changes in the excretion of citrate and magnesium as well
as in the relative supersaturation of brushite which were
not achieved by the tap water regimen. To the contrary, tap
water
produced an unfavourable change in the magnesium
excretion. The group which benefited most were male stone
formers in whom 9 risk factors were favourably altered by
the mineral water protocol. It is concluded that mineral
water containing calcium and magnesium, such as that used
in this study, deserves to be considered as a possible
therapeutic or prophylactic agent in calcium oxalate kidney
stone disease.
Induction of renal
damage in rats by a diet deficient in
antioxidants
Sadava D.; Luo P.-W.; Casper J.
Keck Science Center, 925 N. Mills Ave.,Claremont, CA 91711
United States
Nutrition Research (USA), 1996, 16/9 (1607-1612)
Male albino rats, age 28 days, were fed a diet
containing both vitamin E (10 g/kg) and selenium (5 mg/kg)
or a diet lacking these antioxidants. Animals were examined
for renal function after 4, 8, 12 and 16 wk on the
respective diets. After 8 wk, animals on the deficient diet
weighed less than controls (15%, p<0.01), and this
became more pronounced by 16 weeks (25%, p<0.01).
Expressed on a body weight basis, kidney wet weights did
not differ between the two groups of animals. Urine volume
increased in the animals fed the deficient diet at 8 weeks
(66%, p<0.01) and this was maintained at 16 weeks
(35%, p<0.01). Similar increases were observed for
the rates of excretion of urinary total protein (77%
elevation at 16 wk, p<0.01) and urinary acid
phosphatase (51% elevation, p<0.01). At 16 wk, the
specific activity of renal acid phosphatase in the animals
given the deficient diet was reduced in cortex (57%,
p<0.01) and medulla (20%,
p<0.01), but not in papilla. These data indicate
that dietary antioxidant deficiency causes progressive and
pronounced renal damage.
[Homeostasis of
antioxidant status in hemodialysis patients].
[Article in Japanese]
Saionji K, Sato T, Higurashi H, Iizuka K.
Department of Laboratory Medicine, National Defense
Medical College, Tokorozawa.
Rinsho Byori 1999 May;47(5):461-6
Oxidative stress, which occurs when there is excessive
free-radical production or low antioxidant levels, makes
significant contributions to pathogenesis in many human
diseases. Cardiovascular disease is the major cause of
mortality in patients receiving hemodialysis. For these
patients, oxidative stress and increased lipid peroxidation
may contribute to increased risk of atherosclerosis. The
aim of this study was to determine if hemodialysis patients
were associated with disturbance of homeostasis of
antioxidant status. In this experiment, total antioxidant
status of serum is measured by its ability to inhibit
generation of free radicals from
2,2'-amino-di-[3-ethylbenzthiazole sulphonate] by
metmyoglobin and hydrogen peroxide. Status of radical
scavengers, such as serum total protein, albumin, uric acid
and total bilirubin, was also measured. Blood were
collected from three different episodes of hemodialysis. In
the first group (n = 29), blood were collected before and
after hemodialysis. In the second group (n = 29), blood
were collected after dialysis and before next hemodialysis.
In the third group (n = 8), blood were collected before
hemodialysis. After last hemodialysis, patients started
ingesting vitamin C and blood were collected before next
hemodialysis. There was a marked reduction of total
antioxidant status after hemodialysis in the first group.
There was a marked increase in total antioxidant status
before next hemodialysis in the second group. High doses of
vitamin C caused increase in total antioxidant status in
the third group. In conclusion, disturbance of homeostasis
of total antioxidant status were observed in patients
receiving hemodialysis. This may play a role in the
pathogenesis in these groups.
Effects of L-carnitine
supplementation on muscular symptoms in hemodialyzed
patients.
Sakurauchi Y, Matsumoto Y, Shinzato T, Takai I, Nakamura
Y, Sato M, Nakai S, Miwa M, Morita H, Miwa T, Amano I,
Maeda K.
Aichi Clinic, Toyohashi, Japan.
Am J Kidney Dis 1998 Aug;32(2):258-64
Various muscle symptoms are well recognized among
patients on maintenance hemodialysis. Carnitine deficiency
may be an important factor of dialysis-associated muscle
symptoms, whereas high-dose L-carnitine supplementation may
result in unphysiologically high plasma levels of carnitine
and carnitine esters. We studied the effect of low-dose
L-carnitine treatment (500 mg/d) on muscle symptoms, plasma
carnitine fractions, and lipid profiles in 30 periodically
dialyzed patients with muscular weakness, fatigue, or
cramps/aches. After 12 weeks of L-carnitine treatment,
about two-thirds of patients had at least some improvement
in muscular symptoms, whereas carnitine fractions were
normal or slightly above normal ranges, but lipid profiles
showed no demonstrable changes. This study also showed the
correlation between plasma-free carnitine deficiency and
months on dialysis. These results suggest that prolonged
low-dose L-carnitine treatment can improve
dialysis-associated muscle symptoms by restoring carnitine
tissue levels and washing out acyl moieties.
Homocysteine
metabolism.
Selhub J.
Jean Mayer USDA Human Nutrition Research Center on Aging,
Tufts University,
Boston, Massachusetts 02111, USA.
selhub_vb@hnrc.tufts.edu
Annu Rev Nutr. 1999;19:217-46.
Homocysteine is a sulfur amino acid whose metabolism
stands at the intersection of two pathways: remethylation
to methionine, which requires folate and vitamin B12 (or
betaine in an alternative reaction); and transsulfuration
to cystathionine, which requires pyridoxal-5'-phosphate.
The two pathways are coordinated by S-adenosylmethionine,
which acts as an allosteric inhibitor of the
methylenetetrahydrofolate reductase reaction and as an
activator of cystathionine beta-synthase.
Hyperhomocysteinemia, a condition that recent
epidemiological studies have shown to be associated with
increased risk of vascular disease, arises from disrupted
homocysteine metabolism. Severe hyperhomocysteinemia is due
to rare genetic defects resulting in deficiencies in
cystathionine beta synthase, methylenetetrahydrofolate
reductase, or in enzymes involved in methyl-B12 synthesis
and homocysteine methylation. Mild hyperhomocysteinemia
seen in fasting conditions is due to mild impairment in the
methylation pathway (i.e. folate or B12 deficiencies or
methylenetetrahydrofolate reductase thermolability).
Post-methionine-load hyperhomocysteinemia may be due to
heterozygous cystathionine beta-synthase defect or B6
deficiency. Early studies with nonphysiological high
homocysteine levels showed a variety of deleterious effects
on endothelial or smooth muscle cells in culture. More
recent studies with human beings and animals with mild
hyperhomocysteinemia provided encouraging results in the
attempt to understand the mechanism that underlies this
relationship between mild elevations of plasma homocysteine
and vascular disease. The studies with animal models
indicated the possibility that the effect of elevated
homocysteine is multifactorial, affecting both the vascular
wall structure and the blood coagulation system.
Association between
plasma homocysteine concentrations and extracranial
carotid-artery stenosis.
Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson
PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ,
Rosenberg IH.
Department of Agriculture Human Nutrition Research Center
on Aging, Tufts
University, Boston, MA 02111.
N Engl J Med. 1995 Feb 2;332(5):286-91.
BACKGROUND. Epidemiologic studies have identified
hyperhomocysteinemia as a possible risk factor for
atherosclerosis. We determined the risk of carotid-artery
atherosclerosis in relation to both plasma homocysteine
concentrations and nutritional determinants of
hyperhomocysteinemia.
METHODS. We performed a cross-sectional study of 1041
elderly subjects (418 men and 623 women; age range, 67 to
96 years) from the Framingham Heart Study. We examined the
relation between the maximal degree of stenosis of the
extracranial carotid arteries (as assessed by
ultrasonography) and plasma homocysteine concentrations, as
well as plasma concentrations and intakes of vitamins
involved in homocysteine metabolism, including folate,
vitamin B12, and vitamin B6. The subjects were classified
into two categories according to the findings in the more
diseased of the two carotid vessels: stenosis of 0 to 24
percent and stenosis of 25 to 100 percent.
RESULTS. The prevalence of carotid stenosis of >
or = 25 percent was 43 percent in the men and 34 percent in
the women. The odds ratio for stenosis of > or = 25
percent was 2.0 (95 percent confidence interval, 1.4 to
2.9) for subjects with the highest plasma homocysteine
concentrations (> or = 14.4 mumol per liter) as
compared with those with the lowest concentrations
(< or = 9.1 mumol per liter), after adjustment for
sex, age, plasma high-density lipoprotein cholesterol
concentration, systolic blood pressure, and smoking status
(P < 0.001 for trend). Plasma concentrations of
folate and pyridoxal-5'-phosphate (the coenzyme form of
vitamin B6) and the level of folate intake were inversely
associated with carotid-artery stenosis after adjustment
for age, sex, and other risk factors.
CONCLUSIONS. High plasma homocysteine concentrations and
low concentrations of folate and vitamin B6, through their
role in homocysteine metabolism, are associated with an
increased risk of extracranial carotid-artery stenosis in
the elderly.
Plasma homocysteine as
a risk factor for dementia and Alzheimer's
disease.
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg
IH, D'Agostino RB, Wilson PW, Wolf PA.
Department of Neurology, Boston University School of
Medicine, MA 02118-2526, USA.
N Engl J Med. 2002 Feb 14;346(7):476-83.
BACKGROUND: In cross-sectional studies, elevated plasma
homocysteine levels have been associated with poor
cognition and dementia. Studies of newly diagnosed dementia
are required in order to establish whether the elevated
homocysteine levels precede the onset of dementia or result
from dementia-related nutritional and vitamin
deficiencies.
METHODS: A total of 1092 subjects without dementia (667
women and 425 men; mean age, 76 years) from the Framingham
Study constituted our study sample. We examined the
relation of the plasma total homocysteine level measured at
base line and that measured eight years earlier to the risk
of newly diagnosed dementia on follow-up. We used
multivariable proportional-hazards regression to adjust for
age, sex, apolipoprotein E genotype, vascular risk factors
other than homocysteine, and plasma levels of folate and
vitamins B12 and B6.
RESULTS: Over a median follow-up period of eight years,
dementia developed in 111 subjects, including 83 given a
diagnosis of Alzheimer's disease. The
multivariable-adjusted relative risk of dementia was 1.4
(95 percent confidence interval, 1.1 to 1.9) for each
increase of 1 SD in the log-transformed homocysteine value
either at base line or eight years earlier. The relative
risk of Alzheimer's disease was 1.8 (95 percent confidence
interval, 1.3 to 2.5) per increase of 1 SD at base line and
1.6 (95 percent confidence interval, 1.2 to 2.1) per
increase of 1 SD eight years before base line. With a
plasma homocysteine level greater than 14 micromol per
liter, the risk of Alzheimer's disease nearly doubled.
CONCLUSIONS: An increased plasma homocysteine level is a
strong, independent risk factor for the development of
dementia and Alzheimer's disease.
Autosomal dominant
polycystic kidney disease: clinical and genetic
aspects.
Sessa A; Ghiggeri GM; Turco AE
Department of Nephrology, G. Gaslini Children's Hospital,
Genova, Italy.
J Nephrol (Italy) Nov-Dec 1997, 10 (6) p295-310
Autosomal dominant polycystic kidney disease (ADPKD) is
an inherited systemic disease caused by at least three
different genes. The renal and extrarenal clinical
manifestations, and the systemic complications due to
cystic and non-cystic abnormalities in ADPKD patients have
been widely investigated. Cellular and molecular aspects of
cystogenetic mechanisms concern epithelial tubular cell
proliferation, remodelling of extracellular matrix, fluid
secretion and accumulation, and relations between cell
proliferation and apoptosis. In vitro studies on
cystogenesis suggest a key role of cell-to-cell or
cell-to-matrix interactions. Surface proteins mediating
cell-to-cell contact, such as E-cadherin (polycystin?),
integrin interactions, growth factors, receptor expression,
are involved in the process of differentiation of the
cellular condition and of the extracellular matrix.
Blocking any one of these complex mechanisms should
influence the orientation and polarization of epithelial
tubular cells and should mediate the inversion of fluid
secretion which ends in renal cystogenesis. ADPKD comprises
at least three phenotypically indistinguishable but
genetically distinct entities, caused by mutations in three
autosomal genes: PKD1 (chromosome 16p13.3) is present in
about 85% of patients; PKD2 (chromosome 4q13q23) in 10%;
PKD3 (unknown chromosome) in a few families. PCR-based
mutation
detection methods, automated DNA sequencing, and other
"functional" methods are used to screen and analyse ADPKD
patients. It is not yet known whether the mutations
identified so far in PKD1 and PKD2 inactivate the genes or
generate an aberrant product. The products of PKD1 and PKD2
genes have been called polycystin 1 and 2. Polycystins are
members of a family of interactive proteins involved in
complex adhesive cell-cell, cell-matrix, protein-protein,
and protein-carbohydrate interactions in the extracellular
compartment, and are involved in the same pathway (ion
channel regulator? ion channel? pore?) where mutations in
only one of the simple genes (PKD3 too?) may cause the
ADPKD phenotype. Genotype-phenotype correlations, in terms
of disease severity and/or progression to end-stage renal
disease, probably depend on other factors, both genetic and
environmental (for instance: DD genotype of the ACE gene in
ADPKD hypertensive patients), that might influence the
clinical course and progression of ADPKD. The hypothesis of
the "two hits" has been proposed to explain at the
molecular level the focal nature of cyst formation. (184
Refs.)
Quality of life during
and between hemodialysis treatments: role of L-carnitine
supplementation.
Sloan RS, Kastan B, Rice SI, Sallee CW, Yuenger NJ,
Smith B, Ward RA, Brier ME, Golper TA.
Department of Medicine, University of Louisville, KY,
USA.
Am J Kidney Dis 1998 Aug;32(2):265-72
End-stage renal disease affects every aspect of a
patient's life, including perception of health and quality
of life. It is likely that a hemodialysis patient's
perceptions of health-related quality of life directly
influence compliance with medical, nursing, and nutritional
prescriptions. Because L-carnitine supplementation is known
to enhance muscle strength and energy in hemodialysis
patients, we hypothesized that L-carnitine supplementation
would enhance a hemodialysis patient's perception of
health-related quality of life. To test this hypothesis, 1
g L-carnitine or placebo was administered orally to 101
patients immediately before and after every hemodialysis
treatment for 6 months. To assess health-related quality of
life from the patient's perspective, the Medical Outcomes
Study Short Form 36 instrument was administered before the
study and at 1.5-month intervals for the duration of the
study. In addition, a 10-item questionnaire designed to
assess common intradialytic symptoms was administered at
the end of each dialysis treatment. Other parameters
analyzed included Kt/V(urea) and level of nutrition. In the
6-month group, oral L-carnitine supplementation had an
early positive effect on general health (P < 0.02)
and physical function (P < 0.03), but the perceived
effect was not sustained throughout the 6 months of the
study. In the 3-month group, L-carnitine supplementation
improved vitality (P < 0.02) and general health (P
< 0.01). There was no association between Kt/V(urea)
and perceived health-related quality of life. Serum albumin
concentration was directly correlated to how patients
perceived the quality of their lives.
A prospective study of
plasma homocyst(e)ine and risk of myocardial infarction in
US physicians.
Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson
B, Ullmann D, Tishler PV, Hennekens CH.
Channing Laboratory, Department of Medicine, Brigham and
Women's Hospital,
Boston, MA.
JAMA. 1992 Aug 19;268(7):877-81.
OBJECTIVE--To assess prospectively the risk of coronary
heart disease associated with elevated plasma levels of
homocyst(e)ine. DESIGN--Nested case-control study using
prospectively collected blood samples.
SETTING--Participants in the Physicians' Health Study.
PARTICIPANTS--A total of 14,916 male physicians, aged 40 to
84 years, with no prior myocardial infarction (MI) or
stroke provided plasma samples at baseline and were
followed up for 5 years. Samples from 271 men who
subsequently developed MI were analyzed for homocyst(e)ine
levels together with paired controls, matched by age and
smoking. MAIN OUTCOME MEASURE--Acute MI or death due to
coronary disease.
RESULTS--Levels of homocyst(e)ine were higher in cases
than in controls (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8
nmol/mL; P = .03). The difference was attributable to an
excess of high values among men who later had MIs. The
relative risk for the highest 5% vs the bottom 90% of
homocyst(e)ine levels was 3.1 (95% confidence interval, 1.4
to 6.9; P = .005). After additional adjustment for
diabetes, hypertension, aspirin assignment, Quetelet's
Index, and total/high-density lipoprotein cholesterol, this
relative risk was 3.4 (95% confidence interval, 1.3 to 8.8)
(P = .01). Thirteen controls and 31 cases (11%) had values
above the 95th percentile of the controls.
CONCLUSIONS--Moderately high levels of plasma
homocyst(e)ine are associated with subsequent risk of MI
independent of other coronary risk factors. Because high
levels can often be easily treated with vitamin
supplements, homocyst(e)ine may be an independent,
modifiable risk factor.
Can lowering
homocysteine levels reduce cardiovascular
risk?
Stampfer, M.J., Malinow, M.R.
N. Engl. J. Med. 1995 Feb 2; 332(5): 328-9.
No abstract available.
Hyperhomocysteinemia in
chronic renal failure patients: relation to nutritional
status and cardiovascular disease.
Suliman ME, Lindholm B, Barany P, Bergstrom J.
Department of Clinical Science, Karolinska Institutet,
Huddinge University
Hospital, Stockholm, Sweden.
Clin Chem Lab Med. 2001 Aug;39(8):734-8.
A moderate increase in plasma total homocysteine (tHcy)
is considered to be an
independent risk factor for cardiovascular disease (CVD)
in the general population. Almost all chronic renal failure
(CRF) patients have plasma concentration of tHcy that is
elevated 3 to 4 times above normal. The prevalence of CVD,
diabetes mellitus, malnutrition and hypoalbuminemia is high
in CRF patients. Previous investigations have focused on
the role of vitamin status on plasma tHcy in CRF patients,
but little information exists on the influence of
nutritional status and hypoalbuminemia on plasma tHcy in
CRF, although a
substantial fraction of tHcy (>70%) is
protein-bound, mainly to albumin. Our study in patients
with end-stage renal disease showed that more than 90% of
the patients had elevated plasma tHcy levels, which were
higher in patients with normal nutritional status than in
malnourished patients. Moreover, plasma tHcy was inversely
correlated with subjective global nutritional assessment
(high values denote malnutrition) and positively correlated
with serum albumin and protein intake. Hence, it seems
likely that serum-albumin is a strong determinant of plasma
tHcy in CRF patients and this may contribute to the lower
tHcy levels in malnourished patients. Patients with
diabetes mellitus had lower
serum-albumin and plasma tHcy than non-diabetic patients,
irrespective whether
they were malnourished or not. Patients with CVD had lower
(although still elevated) plasma tHcy levels than those
without CVD. An explanation may be that the prevalence of
diabetes mellitus, malnutrition and hypoalbuminema, i.e.
factors that decrease tHcy, was higher in patients with
CVD, which may explain why they had less elevated values.
Assuming that hyperhomocysteinemia carries an independent
risk of CVD, this implies that almost all CRF patients are
exposed to this risk. CRF patients with CVD had a higher
prevalence of malnutrition, hypoalbuminemia and diabetes
mellitus, which was associated with a lower plasma Hcy
level. This may explain why plasma tHcy was lower (although
still abnormally high) in patients with CVD than in
patients without CVD. The lower tHcy levels in CVD patients
do not contradict the assumption that hyperhomocysteinemia
is a risk factor for CVD since almost all patients are
exposed to this risk, and other factors might be present
that confound the relationship between the absolute tHcy
levels and CVD. Our findings imply that nutritional status
and serum albumin, as well as the presence of diabetes
mellitus, should be taken into consideration when
evaluating tHcy as a risk factor for CVD in CRF
patients.
Amelioration of renal
lesions associated with diabetes by dietary curcumin
in
streptozotocin diabetic rats.
Suresh Babu P, Srinivasan K.
Department of Biochemistry and Nutrition, Central Food
Technological Research
Institute, Mysore, India.
Mol Cell Biochem. 1998 Apr;181(1-2):87-96.
Curcumin, the coloring principle of the commonly used
spice turmeric (Curcuma longa) was fed at 0.5% in the diet
to streptozotocin-induced diabetic Wistar rats for 8 weeks.
Renal damage was assessed by the amount of proteins
excreted in the urine and the extent of leaching of renal
tubular enzymes: NAG, LDH, AsAT, AlAT, alkaline and acid
phosphatases. The integrity of kidney was assessed by
measuring the activities of several key enzymes of the
renal tissue: glucose-6-phosphate dehydrogenase,
glucose-6-phosphatase, and LDH (Carbohydrate metabolism),
aldose reductase and sorbitol dehydrogenase (polyol
pathway), transaminases, ATPases and membrane PUFA/SFA
ratio (membrane integrity). Data on enzymuria, albuminuria,
activity of kidney ATPases and fatty acid composition of
renal membranes in diabetic condition suggested that
dietary curcumin brought about significant beneficial
modulation of the progression of renal lesions in diabetes.
These findings were also corroborated by histological
examination of kidney sections. It is inferred that this
beneficial ameliorating influence of dietary curcumin on
diabetic nephropathy is possibly mediated through its
ability to lower blood cholesterol levels.
Oral calcium supplement
decreases urinary oxalate excretion in patients with
enteric hyperoxaluria.
Takei K, Ito H, Masai M, Kotake T.
Department of Urology, Chiba University School of
Medicine, Ichihara Hospital,
Ichihara, Chiba, Japan.
Urol Int. 1998;61(3):192-5.
We studied the effect of oral calcium supplementation in
patients with enteric hyperoxaluria. Three patients with
renal stone events following ileal resection were given
oral calcium supplement. One of the three patients was put
on a low-fat diet. The treatment reduced urinary oxalate
excretion to the normal range. Subsequently, 2 patients
reduced the dose of calcium supplementation at their own
discretion and consequently developed renal stones again
together with hyperoxaluria. Based on these observations,
we believe that an adequate dose of calcium can normalize
urinary oxalate excretion.
Effect of dietary soy
protein and genistein on disease progression in mice
with
polycystic kidney disease.
Tomobe K, Philbrick DJ, Ogborn MR, Takahashi H, Holub
BJ.
Department of Human Biology and Nutritional Sciences,
University of Guelph,
Ontario, Canada.
Am J Kidney Dis. 1998 Jan;31(1):55-61.
The effects of feeding a soy protein isolate or
genistein, an isoflavonoid present in soy protein, on cyst
development were examined in the DBA/2FG-pcy (pcy) mouse,
an accepted animal model of polycystic kidney disease,
before the appearance of clinical symptoms. In study 1,
60-day-old male pcy mice were evenly divided into two
groups and fed semipurified diets, based on casein or a soy
protein isolate (15 g protein/100 g diet) for 90 days. In
study 2, the animals were fed a casein-based diet (25 g
casein/100 g diet) with or without genistein (0.05 g/100 g
diet) for 60 days. In study 1, total kidney weight
and
kidney weight relative to body weight were significantly
reduced (by 24% to 25%)
in the animals fed the soy protein-based diet, relative to
the casein-fed group, as was kidney water content (by 38%).
In addition, mean cyst volume, as measured by morphometry,
were lower (by 25%) in kidneys from the soy protein-fed
group. No differences were found between these two groups
with respect to final body weight, plasma creatinine, and
protein content; however, plasma urea values were
significantly lower in the soy protein-fed animals.
Genistein supplementation of a casein-based diet in study 2
did not reduce the renal enlargement and cyst development
associated with progression of polycystic kidney disease.
These results suggest that soy protein is effective in
retarding cyst development in the pcy mouse and that this
beneficial effect may be unrelated to its genistein
content.
Taurine: A therapeutic
agent in experimental kidney disease
Trachtman H.; Sturman J.A.
Schneider Children's Hospital, Division Nephrology, SCH
365, 269-01 76th Avenue, New Hyde Park, NY 11040 USA
Amino Acids (Austria), 1996, 11/1 (1-13)
Taurine is an abundant free amino acid in the plasma and
cytosol. The kidney plays a pivotal role in maintaining
taurine balance. Immunohistochemical studies reveal a
unique localization pattern of the amino acid along the
nephron. Taurine acts as an antioxidant in a variety of in
vitro and in vivo systems. It prevents lipid peroxidation
of glomerular mesangial cells and renal tubular epithelial
cells exposed to high glucose or hypoxic culture
conditions. Dietary taurine supplementation ameliorates
experimental renal disease including models of refractory
nephrotic syndrome and diabetic nephropathy. The beneficial
effects of taurine are mediated by its antioxidant action.
It does not attenuate ischemic or nephrotoxic acute renal
failure or chronic renal failure due to sub-total ablation
of kidney mass. Additional work is required to fully
explain the scope and mechanism of action of taurine as a
renoprotective agent in experimental kidney disease.
Clinical trials are warranted to determine the usefulness
of this amino acid as an adjunctive treatment of
progressive glomerular disease and diabetic
nephropathy.
Folic acid
fortification of the food supply. Potential benefits and
risks for the elderly population.
Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub
J.
Jean Mayer US Department of Agriculture Human Nutrition
Research Center on Aging at Tufts University, Boston, Mass
02111, USA.
JAMA. 1996 Dec 18;276(23):1879-85
OBJECTIVE: To estimate the potential benefits and risks
of food folic acid fortification for an elderly population.
Benefits are expected through the improvement of folate and
homocysteine status, but there is also a risk of masking or
precipitating clinical manifestations related to vitamin
B12 deficiency with increasing exposure to folic acid.
DESIGN: Cross-sectional analysis, with projected change
at various levels of folic acid fortification.
SETTING: Participants in the Framingham Heart Study
original cohort.
PARTICIPANTS: A total of 747 subjects aged 67 to 96
years who both completed usable food frequency
questionnaires and had blood concentrations of B vitamins
and homocysteine measured.
MAIN OUTCOME MEASURES: Projected blood folate and
homocysteine concentrations and combined high folate intake
and low plasma vitamin B12 concentration.
RESULTS: Percentages of this elderly population with
folate intake below 400 microg/d are projected to drop from
66% at baseline to 49% with 140 microg of folate per 100 g
of cereal-grain product, to 32% with 280 microg, to 26%
with 350 microg, and to 11% with 700 microg. Percentages
with elevated homocysteine concentrations (>14
micromol/L) are projected to drop from 26% at baseline to
21% with 140 microg of folate per 100 g, to 17% with 280
microg, to 16% with 350 microg, and to 12% with 700 microg.
Without fortification, the prevalence of combined high
folate intake (>1000 microg/d) and low plasma
vitamin B12 concentration (<185 pmol/L [<250
pg/mL]) was 0.1%. This is projected to increase to 0.4%
with folate fortification levels of 140 to 350 microg/100 g
and to 3.4% with 700 microg.
CONCLUSION: The evidence suggests that, at the level of
140 microg/100 g of cereal-grain product mandated by the
Food and Drug Administration, the benefits of folate
fortification, through projected decreases in homocysteine
level and heart disease risk, greatly outweigh the expected
risks. However, quantification of the actual risks
associated with vitamin B12 deficiency remains elusive.
Before higher levels of folic acid fortification are
implemented, further research is needed to better
understand the clinical course of various forms of vitamin
B12 deficiency, to measure the potential effect of high
folate intake on this course, and to identify
cost-effective approaches to the identification and
treatment of all forms of vitamin B12 deficiency.
[Routine determination
of homocysteine in plasma. A new and improved possibility
for risk evaluation and diagnosis of common
diseases] [Article in Norwegian]
Ueland PM, Refsum H, Ulvik RJ.
Laboratorium for klinisk biokjemi, Haukeland sykehus,
Bergen.
Tidsskr Nor Laegeforen. 1992 Sep 30;112(23):2977-80.
The performance of a rapid, fully automated HPLC assay
for total homocysteine in plasma has made it possible to
offer this analysis as a routine laboratory test. The
reference interval in fasting individuals is 7-14 mumol/l.
In EDTA-plasma, homocysteine remains stable for up to four
days at room temperature. The most important indications
for analyzing homocysteine are deficiency of vitamin B12 or
folate, premature cardiovascular disease and inherited
homocystinuria. The clinical usefulness of the assay is
based on the fact that the intracellular metabolism of
homocysteine is dependent on vitamin B12, folate and
vitamin B6. Moreover, homocysteine may be an atherogenic
agent, and there is increasing evidence that a high level
of homocysteine in plasma is an independent risk factor for
developing premature atherosclerotic disease.
Ginkgo biloba extract
attenuates the development of hypertension in
deoxycorticosterone acetate-salt hypertensive
rats.
Umegaki K, Shinozuka K, Watarai K, Takenaka H, Yoshimura
M, Daohua P, Esashi T.
Division of Applied Food Research, The National Institute
of Health and
Nutrition, Tokyo, Japan. umegaki@nih.go.jp
Clin Exp Pharmacol Physiol. 2000 Apr;27(4):277-82.
1. We examined the effects of Ginkgo biloba extract
(GBE) on the development of hypertension, platelet
activation and renal dysfunction in deoxycorticosterone
acetate (DOCA)-salt hypertensive rats. Both DOCA-salt
hypertensive rats and normotensive rats were fed a 2% GBE
diet for 20 days. Blood pressure (BP) was measured by two
methods, namely by the tail-cuff and telemetry methods. 2.
Development of hypertension was attenuated in rats fed a 2%
GBE diet. In addition, an increase in heart weight, an
indicator of sustained high BP, was inhibited significantly
by feeding of the GBE diet. 3. Decreases in
5-hydroxytryptamine content in platelets, a marker of
platelet activation in
vivo associated with hypertension, were also prevented by
feeding of the GBE diet. Ginkgo biloba extract itself did
not inhibit ADP- and collagen-induced platelet aggregation
examined in vitro. Feeding of the GBE diet tended to
inhibit increases in plasma urea nitrogen due to
hypertension. 4. The telemetry study demonstrated that BP
and heart rate (HR) showed a clear circadian rhythm and the
antihypertensive effect of GBE was prominent in the
daytime, a resting period for rats. This anti-hypertensive
effect of GBE was not detected in normotensive rats. In
contrast, the inhibitory effect of GBE on HR was
independent of time and was observed in both normotensive
and hypertensive rats. 5. These results indicate that GBE
has an anti-hypertensive and bradycardiac action, which are
time dependent and independent, respectively. Thus, it
appears that the chronopharmacological action of GBE may be
ascribed not to pharmacokinetic factors, but rather to a
circadian susceptibility rhythm to GBE in DOCA-salt
hypertensive rats.
USRDS 2001 Annual Data
Report
USRDS.
2001 Nov 21. U.S. Renal Data System. Bethesda, MD:
National Institute of Diabetes and Digestive and Kidney
Diseases/National Institutes of Health (www.usrds.org).
Cytokines and the
immune response.
Van der Meide PH, Schellekens H.
Biomedical Primate Research Centre (BPRC), Rijswijk, The
Netherlands.
Biotherapy. 1996;8(3-4):243-9.
Cytokines participate in many physiological processes
including the regulation of immune and inflammatory
responses. These effector molecules are produced
transiently and locally controlling the amplitude and
duration of the response. A variety of experiments has
shown that excessive or insufficient production may
significantly contribute to the pathophysiology of a range
of diseases. Particularly cytokines released by CD4+ T
cells at the onset of an immune response are thought to be
decisive for pathological or physiological consequences.
The meeting in Budapest was focussed on cytokines known to
contribute to the pathophysiology of autoimmune diseases,
infectious diseases and allograft rejection (e.g., IL-1,
IL-4, IL-6, IL-10, IL-12, TNF-alpha and IFN-alpha, -beta,
-gamma). A central role for IFN-gamma in autoimmunity was
suggested by blocking experiments in vivo using monoclonal
antibodies and soluble forms of the IFN-gamma receptor
(IFN-gamma SR). These agents ameliorated disease
development in a variety of experimental autoimmune
diseases in rodents. In a mouse model for the human disease
Myasthenia gravis, IFN-alpha was found to reduce both the
incidence and progression of the disease. Treatment of R.
aurantiacus-infected mice with anti-IL-4 monoclonal
antibodies (mAbs) was reported to interfere with the
regression of granulomas in spleen and liver, most likely
through inadequate IL-4-mediated suppression of IFN-gamma
production. In addition, it was shown that mice with
disrupted IFN-gamma R genes died rapidly after infection
with the BCG strain of M. bovis, whereas normal mice
survived the infection. IL-12 was found to be the main
inductor of IFN-gamma during the lethal Shwartzman
reaction. TNF-alpha was identified as the principal cause
of mortality after the second injection with LPS. In a
variety of studies examining the role of cytokines in the
pathogenesis of AIDS, much
attention was given to the in vitro effects of HIV-1
and/or the HIV-1 viral membrane protein gp120 on triggering
cytokine production by peripheral blood leukocytes (PBLs)
and purified monocytes/macrophages (Mo) originating from
healthy donors. Gp120 as a sole agent significantly
suppressed IFN-gamma production by mitogen-stimulated PBLs
and induced the production of IFN-alpha in cultures of
normal human peripheral blood mononuclear cells (PBMCs). In
a human macrophage cell line, TNF-alpha exerted a
stimulatory effect on viral replication and programmed cell
death induced by HIV-1 which was potentiated by the
simultaneous incubation with IFN-gamma. Upon transfection
of human PBLs and CD4+ T cells with a retroviral vector
encoding human IFN-beta, a notable reduction in reverse
transcriptase activity after HIV-1 challenge was observed.
Gp120 was also found to induce both IL-6 and TNF-alpha
expression and to induce morphological changes reminiscent
for apoptosis in primary astrocytes and in a re-aggregated
human brain cell model, suggesting a role for these
cytokines in the neuropathology of AIDS dementia. Moreover,
data were presented indicating that cytokine-induced
expression of cell adhesion molecules (e.g., ICAM-1) in
HIV-1 infected U 937 cells leads to high level
incorporation of this molecule in the membrane of the viral
progeny which may play a role in the attachment of such
virions to CD4-negative cells.
Effect of folic acid
and betaine on fasting and postmethionine-loading
plasma
homocysteine and methionine levels in chronic
haemodialysis patients.
van Guldener C, Janssen MJ, de Meer K, Donker AJ,
Stehouwer CD.
Department of Nephrology, Vrije Universiteit, Amsterdam,
The Netherlands.
J Intern Med. 1999 Feb;245(2):175-83.
OBJECTIVES: To study fasting and postmethionine-loading
(increment and
decrement) plasma homocysteine levels in end-stage renal
disease (ESRD) patients in relation to B-vitamin status and
after folic acid treatment without or with betaine.
DESIGN: Plasma total homocysteine (tHcy) and methionine
levels were measured in chronic haemodialysis patients
after an overnight fast, and 6 and 24 h after an oral
methionine load (0.1 g kg-1). The patients were
subsequently randomized to treatment with folic acid 5 mg
daily with or without betaine 4 g daily, and the loading
test was repeated after 12 weeks. The patients were then
re-randomized to treatment with 1 or 5 mg folic acid daily
for 40 weeks, after which a third loading test was
performed.
SETTING: Haemodialysis unit of university hospital and
centre for haemodialysis.
SUBJECTS: Twenty-nine consecutive maintenance (>
3 months) haemodialysis patients, not on folic acid
supplementation, 26 of whom completed the study.
RESULTS: At baseline, the mean fasting, the 6 h postload
and the 6 h postload increment plasma tHcy levels were
increased as compared with those in healthy controls (46.8
+/- 6.9 (SEM), 92.8 +/- 9.1 and 46.0 +/- 4.2 mumol L-1,
respectively) and correlated with serum folate (r = -0.42,
P = 0.02; r = -0.61, P = 0.001 and r = -0.54, P = 0.003,
respectively), but not with vitamin B6 or vitamin B12. At
week 12, these variables had all decreased significantly.
Betaine did not have additional homocysteine-lowering
effects. At week 52, fasting and postload tHcy levels did
not differ significantly between patients on 1 or 5 mg
folic acid daily. Plasma tHcy half-life and plasma
methionine levels after methionine loading were not altered
by folic acid treatment.
CONCLUSIONS: In chronic haemodialysis patients, fasting
as well as postmethionine-loading plasma tHcy levels depend
on folate status and decrease after folic acid therapy.
Increased postload homocysteine levels in these patients
therefore do not necessarily indicate an impaired
transsulphuration capacity only; alternatively, folate may
indirectly influence transsulphuration. The elucidation of
the complex pathogenesis of hyperhomocysteinaemia in
chronic renal failure requires further investigation.
Hyperhomocysteinemia,
vascular pathology, and endothelial
dysfunction.
van Guldener C, Stehouwer CD.
Department of Internal Medicine, University Hospital and
Institute for
Cardiovascular Research Vrije Universiteit, Amsterdam, The
Netherlands.
CDA.stehouwer@azvu.nl
Semin Thromb Hemost. 2000;26(3):281-9.
Hyperhomocysteinemia has been associated with premature
atherothrombotic vascular disease. It is not known whether
hyperhomocysteinemia induces a distinct type of vascular
disease. Its interaction, if any, with traditional risk
factors also remains unclear. The pathophysiological
mechanisms linking hyperhomocysteinemia to vascular disease
have been extensively studied in vitro and in animals. From
these studies, it has been suggested that homocysteine
limits the bioavailability of nitric oxide (NO), increases
oxidative stress, stimulates smooth cell proliferation, and
alters elastic wall properties. The relevance of these
proposed mechanisms in vivo is unclear, because clinical
studies have yielded controversial results with regard to
the relation between plasma homocysteine levels and indices
of endothelial function, such as brachial artery
flow-mediated vasodilatation and plasma levels of
endothelium-derived marker proteins. Up till now, there
have been no controlled data on the effects of
homocysteine-lowering treatment on vascular function or
clinical end points. The precise mechanisms (if any) by
which homocysteine mediates its adverse vascular effects
are in fact unknown but may relate to impaired endothelial
and smooth muscle cell function.
Dietary phytoestrogens:
a possible role in renal disease protection.
Velasquez MT, Bhathena SJ.
Am J Kidney Dis. 2001 May;37(5):1056-68.
There is growing evidence that dietary phytoestrogens
have a beneficial role in chronic renal disease. This
review summarizes the recent findings from dietary
intervention studies performed in animals and humans
suggesting that consumption of soy-based protein rich in
isoflavones and flaxseed rich in lignans retards the
development and progression of chronic renal disease. In
several animal models of renal disease, both soy protein
and flaxseed have been shown to limit or reduce proteinuria
and renal pathological lesions associated with progressive
renal failure. In studies of human subjects with different
types of chronic renal disease, soy protein and flaxseed
also appear to moderate proteinuria and preserve renal
function. However, most of these clinical trials were of
relatively short duration and involved a small number of
patients. Furthermore, it is not clear whether the renal
protective effects of soy protein and flaxseed are caused
by the isoflavones (daidzein and genistein) and lignans
(matairesinol and secoisolariciresinol) or some other
component. The biochemistry, metabolism, and mechanisms of
actions of isoflavones and lignans are discussed.
Isoflavones and lignans appear to act through various
mechanisms that modulate cell growth and proliferation,
extracellular matrix synthesis, inflammation, and oxidative
stress. Some of these actions have been shown in vitro, but
studies of the mechanisms operative in vivo are lacking.
The diversity of cellular actions of isoflavones and
lignans supports their protective effects in a variety of
experimental and human types of chronic renal disease.
Further investigations are needed to evaluate their
long-term effects on renal disease progression in patients
with chronic renal failure.
Curcumin prevents
adriamycin nephrotoxicity in rats.
Venkatesan N, Punithavathi D, Arumugam V.
Department of Biochemistry, Central Leather Research
Institute, Madras, India.
Br J Pharmacol. 2000 Jan;129(2):231-4.
The present study investigated the effect of curcumin on
adriamycin (ADR) nephrosis in rats. The results indicate
that ADR-induced kidney injury was remarkably prevented by
treatment with curcumin. Treatment with curcumin markedly
protected against ADR-induced proteinuria, albuminuria,
hypoalbuminaemia and hyperlipidaemia. Similarly, curcumin
inhibited ADR-induced increase in urinary excretion of
N-acetyl-beta-D-glucosaminidase (a marker of renal tubular
injury), fibronectin and glycosaminoglycan and plasma
cholesterol. Curcumin restored renal function in ADR rats,
as judged by the increase in GFR. The data also
demonstrated that curcumin protected against ADR-induced
renal injury by suppressing oxidative stress and increasing
kidney glutathione content and glutathione peroxidase
activity. In like manner, curcumin abolished ADR-stimulated
kidney microsomal and mitochondrial lipid peroxidation.
These data suggest that administration of curcumin is a
promising approach in the treatment of nephrosis caused by
ADR.
Homocysteine metabolism
and risk of myocardial infarction: relation with vitamins
B6, B12, and folate.
Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH,
Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett
WC.
Department of Epidemiology and Public Health, Agricultural
University,
Wageningen, Netherlands.
Am J Epidemiol. 1996 May 1;143(9):845-59.
Elevated plasma homocyst(e)ine levels are an independent
risk factor for vascular disease. In a case-control study,
the authors studied the associations of fasting plasma
homocyst(e)ine and vitamins, which are important cofactors
in homocysteine metabolism, with the risk of myocardial
infarction. The cases were 130 Boston area patients
hospitalized with a first myocardial infarction and 118
population controls, less than 76 years of age, enrolled in
1982 and 1983. Dietary intakes of vitamins B6, B12, and
folate were estimated from a food frequency questionnaire.
After adjusting for sex and age, the authors found that the
geometric mean plasma homocyst(e)ine level was 11% higher
in cases compared with controls (p = 0.006). There was no
clear excess of cases with extremely elevated levels. The
age- and sex-adjusted odds ratio for each 3-mumol/liter
(approximately 1 standard deviation) increase in plasma
homocyst(e)ine was 1.35 (95% confidence interval 1.05-1.75;
p trend = 0/007). After further control for several risk
factors, the odds ratio was not affected, but the
confidence interval was wider and the p value for trend was
less significant. Dietary and plasma levels of vitamin B6
and folate were lower in cases than in controls, and these
vitamins were inversely associated with the risk of
myocardial infarction, independently of other potential
risk factors. Vitamin B12 showed no clear association with
myocardial infarction, although methylmalonic acid levels
were significantly higher in cases. Comparing the mean
levels of several homocysteine metabolites among cases and
controls, the authors found that impairment of
remethylation of homocyst(e)ine (dependent of folate and
vitamin B12 rather than on vitamin B6-dependent
transsulfuration) was the predominant cause of high
homocyst(e)ine levels in cases. Accordingly, plasma folate
and, to a lesser extent, plasma vitamin B12, but not
vitamin B6, correlated inversely with plasma
homocyst(e)ine, even for concentrations at the high end of
normal values. These data provide further evidence that
plasma homocyst(e)ine is an independent risk factor for
myocardial infarction. In this population, folate was the
most important determinant of plasma homocyst(e)ine, even
in subjects with apparently adequate nutritional status of
this vitamin.
Can renal replacement
be deferred by a supplemented very low protein
diet?
Walser M, Hill S.
Department of Pharmacology and Molecular Sciences, Johns
Hopkins School of
Medicine, Baltimore, Maryland 21205, USA.
mwalser@bs.jhmi.edu
J Am Soc Nephrol 1999 Jan;10(1):110-6
Patients with chronic renal failure are commonly started
on renal replacement therapy (RRT) as soon as (or, in some
centers, before) the usual criteria for severity are met,
i.e., GFR <10 ml/min for nondiabetic patients and
<15 ml/min for diabetic patients. To determine
whether RRT can safely be deferred beyond this point,
adults with all types of chronic renal failure who met
these criteria on presentation (23 patients) or who reached
these levels of severity during treatment (53 patients)
were managed conservatively until RRT was judged necessary
by their chosen dialysis or transplantation team, without
input into this decision from the present authors. Patients
were prescribed a very low protein diet (0.3 g/kg) plus
supplemental essential amino acids and/or ketoacids and
followed closely. The intervals between the time at which
GFR became less than 10 ml/min (15 ml/min in diabetic
patients) and the date at which renal replacement therapy
was started were used as estimates of renal survival on
nutritional therapy. Kaplan-Meier analysis showed median
renal survival of 353 d. Acidosis and hypercholesterolemia
were both predictive of shorter renal survival. Signs of
malnutrition did not develop. Final GFR averaged 5.6
1.9
ml/min. Two patients died; thus, annual mortality was only
2.5%. Hospitalizations totaled 19 in 93 patient-years of
treatment, or 0.2 per year. Thus, these well motivated
patients with GFR <10 ml/min (<15 ml/min in
diabetic patients) were safely managed by diet and close
follow-up for a median of nearly 1 yr without dialysis. It
is concluded that further study of this approach is
indicated.
[Levels of L-carnitine
in serum of patients with chronic renal failure treated by
hemodialysis (HD)]. [Article in Polish]
Wanic-Kossowska M, Bombicki K, Koziol L, Czarnecki
R.
Klinika Nefrologii Instytutu Chorob Wewnetrznych AM im. K.
Marcinkowskiego w
Poznaniu.
Pol Arch Med Wewn 1998 Apr;99(4):314-22
Low serum levels of the carnitine in chronic uremic
patients treated by hemodialysis is one of the causes of
muscle weakness. In 50 patients with chronic renal failure
treated by HD and in 13 nondialyzed patients EMG and
measurement of nerve conduction velocity were performed. In
25 of 50 patients treated with HD and in 13 non-dialyzed
patients serum concentration of free and total carnitine
were measured. In HD patients serum level of carnitine was
significantly lower as compared to the control group of
healthy subjects and to the nondialyzed patients. In all
patients the EMG investigations showed the traits of the
neurogenic atrophy of the muscles. The correlation between
the amplitude of muscle potentials and serum levels of
carnitine suggests that the depletion of carnitine may play
a role in severity uremic myopathy.
Antioxidants in the
prevention of renal disease.
Wardle EN.
Ren Fail. 1999 Nov;21(6):581-91.
In view of the role of oxidative processes in inflicting
damage that leads to
glomerulosclerosis and renal medullary interstitial
fibrosis, more attention could be paid to the use of
antioxidant food constituents and the usage of drugs with
recognized antioxidant potential. In any case
atherosclerosis is an important component of chronic renal
diseases. There is a wide choice of foods and drugs that
could confer benefit. Supplementation with vitamins E and
C, use of soy protein diets and drinking green tea could be
sufficient to confer remarkable improvements.
Homocysteine and
atherothrombosis.
Welch, G.N., Loscalzo, J.
N. Engl. J. Med. 1998 Apr 9; 338(15): 1042-50.
No abstract available.
Betaine in the
treatment of homocystinuria due to
5,10-methylenetetrahydrofolate reductase
deficiency.
Wendel U, Bremer HJ.
Eur J Pediatr. 1984 Jun;142(2):147-50.
In a 3-year-old mentally retarded girl with
homocystinuria due to 5,10-methylenetetrahydrofolate
reductase deficiency among different therapeutic approaches
only treatment with betaine (15-20 g/day) resulted in a
satisfactory biochemical response. Betaine improved
homocysteine remethylation and thus lowered plasma
homocystine to trace amounts and normalized the previously
very low plasma methionine concentration. This biochemical
response was associated with a clinical improvement
although she remained mentally retarded.
Homocystinuria--the
effects of betaine in the treatment of patients not
responsive to pyridoxine.
Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA.
N Engl J Med. 1983 Aug 25;309(8):448-53.
The treatment of homocystinuria that is not responsive
to pyridoxine is not usually biochemically or clinically
successful, and vascular, ocular, and skeletal
complications commonly supervene. Persistent marked
homocysteinemia appears to be the most important
biochemical disturbance leading to these complications. Ten
patients with cystathionine beta-synthase deficiency that
was not responsive to pyridoxine and one patient with
homocystinuria due to a defect in cobalamin metabolism were
treated with 6 g daily of betaine added to conventional
therapy, to improve homocysteine remethylation. All
patients had a substantial decrease in plasma total
homocysteine levels (P less than 0.001) and an increase in
total cysteine levels (P less than 0.001). Changes in
plasma methionine concentrations were variable. Fasting
levels of plasma amino acids became normal in two patients,
and in six there was immediate clinical improvement. There
were no unwanted effects. We conclude that treatment of
homocystinuria that is not responsive to pyridoxine and of
disorders of homocysteine remethylation should include
betaine in adequate doses to ensure maximum lowering of
elevated plasma homocysteine levels.
Why oral calcium
supplements may reduce renal stone disease: report of a
clinical pilot study.
Williams CP, Child DF, Hudson PR, Davies GK, Davies MG,
John R, Anandaram PS, De Bolla AR.
Department of Medical Biochemistry, Wrexham Maelor
Hospital NHS Trust, Wrexham LL13 7TD, UK.
clive.williams@new-tr.wales.nhs.uk
J Clin Pathol. 2001 Jan;54(1):54-62.
AIMS: To investigate whether increasing the daily
baseline of gut calcium can cause a gradual downregulation
of the active intestinal transport of calcium via reduced
parathyroid hormone (PTH) mediated activation of vitamin D,
and to discuss why such a mechanism might prevent calcium
oxalate rich stones. To demonstrate the importance of
seasonal effects upon the evaluation of such data.
METHODS: Within an intensive 24 hour urine collection
regimen, daily calcium supplementation (500 mg) was given
to five stone formers for a 10 week period during a six
month crossover study. In a further population of patients
on follow up for previous renal stone disease, observations
were made on 1066 24 hour urine samples collected over five
years in respect of seasonal effects relevant to the
interpretation of the study.
RESULTS: In the group of patients on calcium supplements
the following results were found. During calcium
supplementation, the proportion of urine calcium to oxalate
was higher (increased calcium to oxalate molar ratio), the
24 hour urine product of calcium and oxalate did not rise,
and urine oxalate was lower during the first six weeks of
supplementation. Twenty four hour urine calcium was 10.2%
higher than baseline in the final four weeks of the 10
weeks of supplementation. Twenty four hour urine phosphate
was 11.4% lower during the first six weeks of
supplementation, but then rose while the patients were
still on supplementation; renal tubular reabsorption of
phosphate (TmP/GFR) mirrored the urine phosphate changes
inversely. PTH was higher after stopping supplementation,
but 1,25-(OH)2-cholecalciferol changes were not detected.
In the 1066 urine samples collected over five years the
following results were found. Calcium and oxalate excretion
correlated positively and not inversely. Urine calcium and
phosphate excretion were 5.5% and 2.5% higher,
respectively, in "light" months of the year compared with
"dark" months. A post summer decline in both urine calcium
and urine phosphate was relevant to the interpretation of
the study.
CONCLUSIONS: Regular calcium supplementation does not
raise the product of calcium and oxalate in urine and the
proportion of oxalate to calcium is reduced. The underlying
mechanisms of the changes seen in phosphate, calcium, and
PTH and the observations on 1,25-(OH)2-cholecalciferol are
not clear. Observed changes in phosphate could possibly be
part of a calcium regulating feedback loop operating over a
period of weeks. In evaluating these mechanisms background
seasonal effects are important. It is possible that
"programming" of the gut mucosa in terms of calcium
transport is a major determinant of the relation between
calcium and oxalate concentrations in urine and their
relative abundance. Increased oral calcium, in association
with a reduction of the relative
proportion absorbed, may be pertinent to the prevention of
calcium oxalate rich stones.
Haemolipodialysis.
Wratten ML, Navino C, Tetta C, Verzetti G.
Clinical and Laboratory Research Division, Bellco SpA,
Mirandola, Italy.
wratten.marylou@arcanet.it
Blood Purif 1999;17(2-3):127-33
Haemodialysis is associated with increased oxidant
stress. This appears to be due to (1) an increased
production of free radicals during haemodialysis, (2) a net
reduction of many antioxidants and (3) factors intrinsic to
the uremic state. These alterations can lead to
cardiovascular disease and many of the pathologies
associated with chronic renal failure. Haemolipodialysis
(HLD) is a new haemodialytic technique aimed at reducing
oxidant stress and removing hydrophobic or protein bound
toxins. The technique uses dialysate containing ascorbic
acid (vitamin C) and polyunsaturated unilamellar liposomes
containing
alpha-tocopherol (vitamin E). The liposomes interact with
blood components at the haemodialysis membrane without
passage through the membrane. Vitamin C and vitamin E are
added to the system to protect the cell and plasma
components from reactive oxygen species produced from
activated inflammatory cells. This technique may provide a
new approach in preventing free radical-associated
pathologies in chronic haemodialysis patients.
Effectiveness of green
tea tannin on rats with chronic renal failure.
Yokozawa T, Chung HY, He LQ, Oura H.
Research Institute for Wakan-Yaku, Toyama Medical and
Pharmaceutical University, Japan.
Biosci Biotechnol Biochem. 1996 Jun;60(6):1000-5.
The effects of green tea tannin on nephrectomized rats
were examined. There were increases in blood urea nitrogen,
serum creatinine, and urinary protein, and a decrease in
creatinine clearance in the nephrectomized control rats,
whereas better results for these parameters were obtained
in rats given green tea tannin after nephrectomy,
demonstrating a suppressed progression of the renal
failure. When the renal parenchyma was partially resected,
the remnant kidney showed a decrease in the activity of
radical scavenger enzymes. Green tea tannin, however, was
found to lighten the kidney under such oxidative stress.
Mesangial proliferation and glomerular sclerotic lesions,
which were conspicuous in the rats that were not given
green tea tannin after nephrectomy, were also relieved.
Effects of green tea
tannin on cisplatin-induced nephropathy in LLC-PK1 cells
and rats.
Yokozawa T, Nakagawa T, Lee KI, Cho EJ, Terasawa K,
Takeuchi S.
Research Institute for Wakan-Yaku, Toyama Medical and
Pharmaceutical University, Sugitani, Japan.
yokozawa@ms.toyama-mpu.ac.jp
J Pharm Pharmacol. 1999 Nov;51(11):1325-31.
A study was conducted to clarify whether green tea
tannin ameliorated cisplatin-induced renal injury in terms
of lactate dehydrogenase and malondialdehyde leakage from a
renal epithelial cell line, swine-derived LLC-PK1 cells in
culture. Green tea tannin was shown to suppress the
cytotoxicity of cisplatin, the suppressive effect
increasing with the dose of green tea tannin. The effect of
cisplatin was then investigated in rats given green tea
tannin for 40 days before cisplatin administration and in
control rats given no green tea tannin. In control rats,
blood, urinary and renal parameters and the activities of
antioxidative enzymes in renal tissue deviated from the
normal range, indicating dysfunction of the kidneys. In
contrast, rats given green tea tannin showed decreased
blood levels of urea nitrogen and creatinine, and decreased
urinary levels of protein and glucose, reflecting less
damage to the kidney. In this group, the activity of
catalase in the renal tissue was increased, while
the level of malondialdehyde was decreased, suggesting the
involvement of radicals in the normalizing of kidney
function. Based on the evidence available it appeared that
green tea tannin eliminated oxidative stress and was
beneficial to renal function.
Linkage analysis of
families with autosomal dominant polycystic kidney disease
by KG8-CA marker.
Yuan CF, Lin CY, Chen TW, Yang ML, Ng HT.
Department of Obstetrics and Gynecology, Veterans General
Hospital-Taipei,
Taiwan, R.O.C.
Zhonghua Yi Xue Za Zhi (Taipei). 1997
Sep;60(3):125-9.
BACKGROUND: Autosomal dominant polycystic kidney disease
(ADPKD) is one of the most common genetic diseases of
human. Traditionally, ADPKD is diagnosed by
ultrasonography, computed tomography (CT) or magnetic
resonance imaging (MRI) of kidneys for the presence of
renal cysts. Individuals who carry the defective gene but
have not yet developed cysts in kidney may not be
diagnosed. Genetic analysis reveals it to be caused mostly
by a single-gene disorder of a genetic locus, designated
PKD1. Recently, the genetic locus involving PKD1 has been
identified on chromosome 16p13.3, and has been cloned and
completely sequenced.
METHODS: A pair of primers, KG8-CA, located between
D16S84 and D16S125, was selected and synthesized for the
polymerase chain reaction (PCR) to identify individuals who
may carry the defective locus. The sequence of KG8-CA
primers, was 5'-CTCCCAGGGTGGAGGAAGGTG-3' and
5'-GCAGGCACAGCCAGCTCCGAG- 3'. PCR products were analyzed in
denaturing condition, using gel containing 8% acrylamide
and 7M urea. Autoradiography was carried out to interpret
the results.
RESULTS: Four Chinese families with history of ADPKD
showed different DNA patterns in individuals with ADPKD and
in normal individuals. Among the members in four families
with history of ADPKD, every individual shared a common DNA
band, suggesting that this band was derived from normal
PKD1 allele. On the other hand, individuals diagnosed to
have ADPKD showed one or two additional DNA bands which
migrated differently from the common DNA band and should
therefore be derived from defective ADPKD allele. Previous
studies have shown that the ADPKD allele is highly
polymorphic, as was evident in these family studies.
CONCLUSIONS: Among the members from these four families,
some were clinically normal and had DNA pattern that was
typical to patients with ADPKD. These individuals might
carry the defective PKD1 allele but have not yet developed
the ADPKD symptoms. Therefore, the method described in this
study has diagnostic values for pre-symptomatic individuals
as well as for patients already diagnosed with ADPKD.
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